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Mitochondrial DNA sequence variation and risk of pancreatic cancer.

ABSTRACT: Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases = 286, controls = 283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (P < 0.05) with the strongest finding for mt5460g in the ND2 gene [OR = 3.9; 95% confidence interval (CI), 1.5-10; P = 0.004] which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32; 95% CI, 0.13-0.76; P = 0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (P < 0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (P = 0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.

SUBMITTER: Lam ET

PROVIDER: S-EPMC3271167 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Mitochondrial DNA sequence variation and risk of pancreatic cancer.

Lam Ernest T ET Bracci Paige M PM Holly Elizabeth A EA Chu Catherine C Poon Annie A Wan Eunice E White Krystal K Kwok Pui-Yan PY Pawlikowska Ludmila L Tranah Gregory J GJ

Cancer research 20111215 3

Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases = 286, controls = 283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (P < 0.05) with the strongest find ...[more]

PMID: 22174369

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Project description:Abstract Meningiomas are the most common primary central nervous system tumors. Risk factors include female sex, African American race, a higher body mass index, and exposure to ionizing radiation. Genome-wide association studies have identified two risk loci for meningioma in the nuclear genome (rs12770228 and rs2686876). Whereas mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, research on meningioma is lacking. We examined the association of 42 common (minor allele frequency ≥ 5%) germline mtDNA variants, haplogroups, and genes with meningioma risk in 1,080 controls and 478 cases from a case-control study conducted at medical centers in the southeastern US. Participant DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for meningioma overall, WHO grade 1 (n=409) and WHO grade 2/3 (n=69) meningiomas. Overall, meningioma risk was significantly higher among women (OR=2.86; 95% CI:2.21-3.71) compared to men, higher among African Americans (OR=2.37, 95% CI:1.41-3.99) compared to Caucasians, and higher among those who were overweight (OR=1.48; 95% CI:1.11-1.98) or obese (OR= 1.73; 95% CI:1.26-2.38) compared to those of normal weight. The variant m.16362T >C (rs62581341) in the mitochondrial control region was positively associated with grade 2/3 meningiomas (OR=2.33; 95% CI: 1.14-4.79), but not with grade 1 tumors (OR=0.99; 95% CI:0.64-1.53). Haplogroup L, a marker for African ancestry, was identified among 3.6% of controls and 8.6% of cases and was associated with meningioma risk overall (OR=2.56; 95% CI:1.52-4.30). When stratifying by self-reported race, the association between haplogroup L and meningioma was only apparent among the small number of self-reported Caucasians with this haplogroup (OR=6.68; 95% CI=1.66-26.91) when compared to non-L haplogroups, combined. No other common mtDNA variant (minor allele >5%), haplogroup, or gene was associated with meningioma risk. These findings merit further study.

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Mitochondrial DNA sequence variation and risk of pancreatic cancer.

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Mitochondrial DNA sequence variation and risk of pancreatic cancer.

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